Latent alpha1-antichymotrypsin. A molecular explanation for the inactivation of alpha1-antichymotrypsin in chronic bronchitis and emphysema.
alpha1-Antichymotrypsin is an acute phase protein that protects the tissues from damage by proteolytic enzymes, but previous studies have shown that alpha1-antichymotrypsin within the lungs of patients with chronic bronchitis and emphysema is intact but inactive as an inhibitor. Ammonium sulfate fractionation followed by blue Sepharose and DNA-Sepharose chromatography was used to isolate small amounts of intact, monomeric but inactive alpha1-antichymotrypsin from the plasma of 30 healthy blood donors. This species had a higher DNA binding affinity with more anodal electrophoretic mobility than native alpha1-antichymotrypsin and was conformationally stable against thermal denaturation, 8 M urea, and 7 M guanidinium chloride. The protein was unable to accept synthetic reactive loop peptides, and the reactive loop was resistant to proteolytic cleavage at the P5-P4 bond but could be cleaved between P1' and P3'. These data suggest that this new alpha1-antichymotrypsin species was in a conformation similar to those of the crystallographically determined latent serpins, plasminogen activator inhibitor-1 and antithrombin. alpha1-Antichymotrypsin from lung lavage migrated with the same electrophoretic mobility as the putative latent alpha1-antichymotrypsin, suggesting that this is the inactive conformation described previously in the lungs of patients with chronic bronchitis and emphysema. This conformational transition of alpha1-antichymotrypsin, from an active to an inactive state, within the lung may play an important role in the pathogenesis of chronic lung disease.
Chang
W S
WS
Departments of Medicine and Haematology, University of Cambridge, Medical Research Council Centre, Hills Road, Cambridge CB2 2QH, United Kingdom.
Lomas
D A
DA
D001991:Bronchitis / Q000378:metabolism*; D001992:Bronchoalveolar Lavage Fluid; D002908:Chronic Disease; D018360:Crystallography, X-Ray; D004591:Electrophoresis, Polyacrylamide Gel; D004646:Emphysema / Q000378:metabolism*; D006801:Humans; D011487:Protein Conformation; D000514:alpha 1-Antichymotrypsin / Q000737:chemistry / Q000378:metabolism*
D000514:alpha 1-Antichymotrypsin